1. Field of the Invention
This invention relates to neurobiology, neurology and pharmacology. More particularly, it relates to methods of treating diseases relating to central nervous system myelination by the administration of semaphorin 6A (“Sema6A”) polypeptide.
2. Background Art
Many diseases of the nervous system are associated with demyelination and dysmyelination, including multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelolysis (CPM), Wallerian Degeneration and some inherited diseases such as adrenoleukodystrophy, Alexander's disease, and Pelizaeus Merzbacher disease (PMZ). Among these diseases, MS is the most widespread, affecting approximately 2.5 million people worldwide.
MS generally begins with a relapsing-remitting pattern of neurologic involvement, which then progresses to a chronic phase with increasing neurological damage. MS is associated with the destruction of myelin, oligodendrocytes and axons localized to chronic lesions. The demyelination observed in MS is not always permanent and remyelination has been documented in early stages of the disease. Remyelination of central nervous system (“CNS”) neurons requires oligodendrocytes.
Various disease-modifying treatments are available for MS, including the use of corticosteroids and immunomodulators such as interferon beta. In addition, because of the central role of oligodendrocytes and myelination in MS, there have been efforts to develop therapies to increase oligodendrocyte numbers or enhance myelination. See, e.g., Cohen et al., U.S. Pat. No. 5,574,009; Chang et al., N. Engl. J. Med. 346:165-73 (2002). However, there remains an urgent need to devise additional therapies for MS.
Semaphorins are secreted or membrane-bound proteins that are known to control axon guidance and cell migration. Kerjan et al., Nat. Neursci. 8(11): 1516-1524 (2005). Many transmembrane semaphorins are expressed in the developing CNS, but little is known of their functions in vivo. Id. Class 6 semaphorins comprise four proteins, Sema6A-Sema6D, that are closely related to invertebrate transmembrane semaphorins. Fiore & Puschel. Front. Biosci. 8:2484-2499 (2003). All semaphorins possess a semaphorin (Sema) domain and a plexin-semaphorin-integrin (PSI) domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion.
Plexins are a family of molecules (the plexin family) which are distributed in various animal species. Murakami et al., Dev. Dynam. 220: 246-258 (2001). Plexins are grouped into four sub-families, i.e., plexin-A, -B, -C, and -D. Id. In mouse and human, four members of the plexin-A subfamily (plexin-A1, -A2, -A3, and -A4) have been isolated. See Kameyama et al., Biochem. Biophys. Res. Commun. 226: 396-402 (1996); Kameyama et al., Biochem. Biophys. Res. Commun. 226: 524-529 (1996); Maestrini et al., Proc. Natl. Acad. Sci. USA 93: 674-678 (1996); Tamagnone et al., Cell 99: 71-80 (1999); and Suto et al., Mech. Dev. 120: 385-396 (2003). The ectodomains of the plexin-A subfamily possess a stretch of approximately 500 amino acids (aa) residues which exhibit significant homology to the sema domain shared by semaphorins. Murakami et al., Develop. Dyn. 220: 246-258 (2001). Type-A plexins are known to interact with class 6 semaphorins. Toyofuku et al., Genes Develop. 18: 435-447 (2004). For example, Suto et al. showed that plexin-A4 is a direct receptor for Sema6A. J. Neurosci. 25(14): 3628-3637 (2005).